Pharmaceutical composition

ABSTRACT

Disclosed are novel pharmaceutical compositions containing N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethyl sulfoxide solvate, methods of using the compositions in therapy and processes for preparing the same.

This application is a continuation of U.S. application Ser. No.13/330,949 filed on Dec. 20, 2011, now U.S. Pat. No. 8,580,304, whichclaims the benefit of U.S. Provisional Application No. 61/424,967 filed20 Dec. 2010, which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to solid oral pharmaceutical dosage forms,suitably tablets, suitably capsules, comprisingN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, represented by the following formula (I) andhereinafter referred to as Compound A:

BACKGROUND OF THE INVENTION

N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide,as the un-solvated compound (hereinafter Compound B) is a compound whichis disclosed and claimed, along with pharmaceutically acceptable saltsand solvates thereof, as being useful as an inhibitor of MEK activity,particularly in treatment of cancer, in International Application No.PCT/JP2005/011082, having an International filing date of Jun. 10, 2005;International Publication Number WO 2005/121142 and an InternationalPublication date of Dec. 22, 2005, the entire disclosure of which ishereby incorporated by reference. Compound B is the compound of Example4-1. Compound B can be prepared as described in InternationalApplication No. PCT/JP2005/011082. Compound B can be prepared asdescribed in United States Patent Publication No. US 2006/0014768,Published Jan. 19, 2006, the entire disclosure of which is herebyincorporated by reference. Compound B is the compound of Example 4-1.

Suitably, Compound B is in the form of a dimethyl sulfoxide solvate, orCompound A as defined herein. Suitably, Compound B is in the form of asolvate selected from: hydrate, acetic acid, ethanol, nitromethane,chlorobenzene, 1-pentanol, isopropyl alcohol, ethylene glycol and3-methyl-1-butanol. Solvates and salt forms can be prepared by one ofskill in the art, for example from the description in InternationalApplication No. PCT/JP2005/011082 or United States Patent PublicationNo. US 2006/0014768. Compound A is prepared in Example 4-149 of UnitedStates Patent Publication No. US 2006/0014768.

Solid oral pharmaceutical dosage forms are popular and useful forms ofmedications for dispensing pharmaceutically active compounds. A varietyof such forms are known, including tablets, capsules, pellets, lozenges,and powders.

However, the formulation of an acceptable solid oral pharmaceuticaldosage form on a commercial scale is not straightforward. Whenadministered in vivo, each pharmaceutical compound acts uniquely inregards to therapeutic drug levels. Further, pharmaceutically activecompounds, particularly anti-neoplastic compounds, are often associatedwith undesirable side effects such as; toxicity (e.g. genotoxicity,teratogenicity) and undesirable physical or psychologicalmanifestations. In addition to balancing the drug's unique chemicalproperties with those of the excipients, the drug must be administeredat a specific amount that is sufficient to provide the desiredtherapeutic drug level but less than the amount that presents anunacceptable side effect profile, or within the therapeutic window forthat particular drug. Moreover, the formulation and process ofmanufacture must be such as to provide an integral solid dosage formthat maintains its integrity until used. The solid dosage form must alsopossess acceptable dissolution and disintegration properties so as toprovide the desired profile in use. Pharmaceutically active compoundswith low solubility and/or in solvate form can present particularchallenges in preparing high quality solid dosage forms. Thesechallenges include insufficient and in consistent exposure upon in vivoadministration and desolvation which releases unsolvated compound whichcan exhibit poor pharmacodynamic properties.

It would be desirable to provide Compound A in a solid oralpharmaceutical dosage form on a commercial scale with a desirablepharmacodynamic profile.

SUMMARY OF THE INVENTION

The present invention relates to solid oral pharmaceutical dosage forms,suitably tablets, suitably capsules, comprising a therapeuticallyeffective amount of Compound A. The invention also relates to a processfor making solid oral pharmaceutical dosage forms, suitably tablets,suitably capsules, comprising Compound A.

Another aspect of this invention relates to solid oral pharmaceuticaldosage forms, suitably tablets, suitably capsules, comprising Compound Athat are formulated using excipients, suitably the diluent component,that are substantially free of water, which as used herein and in theclaims includes anhydrous versions of non-anhydrous excipients. Suchsolid oral pharmaceutical dosage forms exhibit improved properties. Suchimproved properties help to ensure safe and effective treatment.

Another aspect of this invention relates to a pharmaceutical tabletcomprising a therapeutically effective amount of Compound A, wherein thetablet is prepared by compression of dry blend, suitably by directcompression or by dry granulation. Such pharmaceutical tablet exhibitsimproved properties. Such improved properties help to ensure safe andeffective treatment. The invention also relates to a method of makingdirect compression and dry granulation pharmaceutical tablets comprisingCompound A.

Another aspect of this invention relates to film coated oralpharmaceutical tablets comprising Compound A, suitably the film coat isan aqueous film coat composition comprising a film-forming polymer andwater as a vehicle, suitably containing a pigment or colorant, suitablyan iron oxide containing pigment or colorant. Such tablets exhibitimproved properties. Such improved properties help to ensure safe andeffective treatment.

Another aspect of this invention relates to solid oral pharmaceuticaldosage forms, suitably tablets, suitably capsules, comprising Compound Ain an amount selected from: 0.5, 1 and 2 mg, by weight of Compound B.Such solid oral pharmaceutical dosage forms exhibit improved properties.Such improved properties help to ensure safe and effective treatment.

Another aspect of this invention relates to solid oral pharmaceuticaldosage forms, suitably tablets, suitably capsules, containing Compound Ain which Compound A is in micronized form. Such solid oralpharmaceutical dosage forms exhibit improved properties. Such improvedproperties help to ensure safe and effective treatment.

Another aspect of this invention relates to solid oral pharmaceuticaldosage forms, suitably tablets, suitably capsules, containing Compound Ain which at least 50% of the Compound A particles have a particle sizeof 30 micron or less, suitably at least 50% of the Compound A particleshave a particle size of 10 micron or less, suitably at least 50% of theCompound A particles have a particle size of 5 micron or less. Suchsolid oral pharmaceutical dosage forms exhibit improved properties. Suchimproved properties help to ensure safe and effective treatment.

Another aspect of the this invention relates to solid oralpharmaceutical dosage forms, suitably tablets, suitably capsules,containing Compound A in which the amount of unsolvated compound (orCompound B as used herein) does not exceed about 20%, suitably theamount of unsolvated compound does not exceed about 15%, suitably theamount of unsolvated compound does not exceed about 10%, suitably theamount of unsolvated compound does not exceed about 5%, suitably theamount of unsolvated compound does not exceed about 2%. Such solid oralpharmaceutical dosage forms exhibit improved properties. Such improvedproperties help to ensure safe and effective treatment.

Another aspect of this invention relates to a method of treating cancerin a mammal, including a human, which method comprises administering toa subject in need thereof a solid oral pharmaceutical dosage form,suitably a tablet, suitably a capsule, of the present invention thatcontains an amount of Compound A selected from: 0.5, 1 and 2 mg, byweight of Compound B.

Another aspect of this invention relates to a method of inhibiting MEK,in a human, which method comprises administering to a subject in needthereof a solid oral pharmaceutical dosage form, suitably a tablet,suitably a capsule, of the present invention that contains an amount ofCompound A selected from: 0.5, 1 and 2 mg, by weight of Compound B.

Also included in the present invention are methods of co-administering asolid oral pharmaceutical dosage form of the present invention withfurther active ingredients, suitably the further active ingredients areanti-neoplastic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the exposure (AUC) data for Compound A in pre-clinicalstudies in a rat model.

FIG. 2 depicts stability data for 1 mg tablets containing Compound Aexposed to four different storage conditions.

DETAILED DESCRIPTION OF THE INVENTION

Compound A presents the formulator with unique concerns when attemptingto formulate this compound into a suitable solid oral pharmaceuticaldosage form, suitably a tablet, suitably a capsule, within thetherapeutic window for Compound A, particularly on a commercial scale.Such concerns include but are not limited to; the tendency of thecompound to revert to an insoluble desolvated form when exposed tomoisture during the formulation process, slow dissolution of thecompound from solid dosage forms, and that Compound A can suffer fromphoto-instability.

Significant realization of these concerns will have an adverse effect onthe in vivo administration of Compound A.

It would be desirable to provide Compound A in tablet form on acommercial scale, since tablets tend to provide greater accuracy ofdosage, convenient administration, increased durability and stabilityduring storage, shorter production time, and economy and efficiency instorage, packaging and shipping. Unfortunately, photo-instability ofCompound A becomes a potential concern in tablet forms.

In one embodiment, the present invention is directed to solid oralpharmaceutical dosage forms that contain Compound A, suitably the soliddosage form is a tablet, suitably the solid dosage form is a capsule,suitably these solid dosage forms are produced on a commercial scale.

It has been found that Compound A can suffer from photo-instability. Thepotential for unacceptable levels of photo-degradation is of particularimportance since photo-catalyzed degradation products may be potentiallytoxic.

It has now been discovered that Compound A tablets that are coated withan aqueous colored film coat, suitably an iron oxide containing coloredfilm coat, for example Opadry® yellow or pink, exhibit improvedphoto-stability. This improved stability leads to a reduction in thelevels of photo-catalyzed degradation products forming upon lightexposure. Such improved stability helps to ensure safe and effectivetreatment.

In one embodiment, the present invention is directed to tabletscontaining Compound A that are coated with an aqueous colored film coat.Suitably these tablet forms are produced on a commercial scale. Thesetablet forms help provide safe and effective treatment.

It has been found that Compound A can cause toxic effects whenadministered in high doses. It has been discovered that Compound A, whenadministered in an amount selected from about 0.5 mg, 1 mg and 2 mg,based on the amount of Compound B, is sufficient to provide the desiredtherapeutic drug level but less than the amount that presents anunacceptable side effect profile, or within the therapeutic window forCompound A.

In one embodiment, the present invention is directed to tabletscontaining Compound A in an amount selected from: about 0.5 mg, 1 mg and2 mg based on the amount of Compound B. These tablet strengths helpprovide safe and effective treatment.

It has been found that Compound A can undergo desolvation duringhandling and formulation resulting in unsolvated Compound B beingformed. Compound B is much less soluble than Compound A, whichnegatively impacts its pharmacodynamics when released from apharmaceutical composition. It has been found that pharmaceuticalformulations, suitably tablets, suitably capsules, in which the amountof desolvated Compound B does not exceed 20%, suitably does not exceed15%, suitably does not exceed 10%, suitably does not exceed 5%, suitablydoes not exceed 2%, when compared to Compound A, provide an acceptablerelease/pharmacodynamic profile.

In one embodiment, the present invention is directed to tabletscontaining Compound B in an amount that does not exceed about 20%,suitably about 15%, suitably about 10%, suitably about 5%, suitablyabout 2% of the amount of Compound A. Such tablets help provide safe andeffective treatment.

It has been found that Compound A can exhibit poor exposure andabsorption upon in vivo administration. It has been found thatpharmaceutical formulations, suitably tablets, suitably capsules, inwhich Compound A is micronized, suitably where at least 50% or theparticles of Compound A are 30 micron or less, suitably at least 50% ofthe particles of Compound A are 10 micron or less, suitably at least 50%of the particles of Compound A are 5 micron or less, provide anacceptable exposure/absorption profile.

In one embodiment, the present invention is directed to tabletscontaining Compound A in micronized form, suitably where at least 50% ofthe particles of Compound A are 30 micron or less, suitably at least 50%of the particles of Compound A are 10 micron or less, suitably at least50% of the particles of Compound A are 5 micron or less. Such tabletshelp provide safe and effective treatment.

As used herein, the term “improved properties” and derivatives thereof,contemplates several advantages to the pharmacokinetic profile of the invivo release of Compound A from a formulation, suitably a solid oralpharmaceutical dosage form, suitably a capsule, suitably a tablet, thatutilizes an aspect of the present invention when compared to aformulation that does not utilize that aspect of the present invention,suitably the formulation is produced on a commercial scale. Examples ofimproved properties include: increased oral bioavailability, improvedphysical and chemical stability, improved photo-stability, a consistentpharmacokinetic profile, an improved pharmacokinetic profile and aconsistent dissolution rate.

As used herein, the term “drug” or “active ingredient” and derivativesthereof, unless otherwise defined, means Compound A orN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide.

As used herein, the term “Compound B” and derivatives thereof, meansN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide,as the free or unsalted and unsolvated compound. Compound B also refersto the amount of free or unsalted and unsolvated compound in an amountof Compound A.

By the term “commercial scale” and derivatives thereof, as used hereinis meant, preparation of a batch scale greater than about 20 kg ofdirect compression mix, suitably greater than 50 kg, suitably greaterthan 75 kg or a batch size suitable to prepare at least about 50,000solid oral pharmaceutical dosage forms, suitably tablets, suitablycapsules, suitably at least 75,000 solid oral pharmaceutical dosageforms, suitably tablets, suitably capsules, suitably at least 100,000solid oral pharmaceutical dosage forms, suitably tablets, suitablycapsules.

The term “effective amount” and derivatives thereof, means that amountof a drug or active ingredient that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought, for instance, by a researcher or clinician. Furthermore, theterm “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder. The term also includes within itsscope amounts effective to enhance normal physiological function.

As used herein, the term “formulation” and derivatives thereof, unlessotherwise defined refers to solid oral pharmaceutical dosage forms,suitably tablets, suitably capsules, of the invention that containCompound A.

By the term “co-administration” as used herein is meant eithersimultaneous administration or any manner of separate sequentialadministration of a solid oral pharmaceutical dosage form containingCompound A, and a further active agent or agents, known to be useful inthe treatment of cancer, including chemotherapy and radiation treatment.The term further active agent or agents, as used herein, includes anycompound or therapeutic agent known to or that demonstrates advantageousproperties when administered to a patient in need of treatment forcancer. As used herein, “further active agent or agents” is usedinterchangeably with further anti-neoplastic agent or agents.Preferably, if the administration is not simultaneous, the compounds areadministered in a close time proximity to each other. Furthermore, itdoes not matter if the compounds are administered in the same dosageform, e.g. one compound may be administered by injection and anothercompound may be administered orally. Suitably, the “co-administration”will consist essentially of a solid oral pharmaceutical dosage formcontaining compound A and a second pharmaceutical dosage form containinga further active agent. Suitably, the “co-administration” will consistessentially of a solid oral pharmaceutical dosage form containingcompound A, a second pharmaceutical dosage form containing a furtheractive agent, and a third pharmaceutical dosage form containing anotherfurther active agent.

Typically, any anti-neoplastic agent that has activity versus asusceptible tumor being treated may be co-administered in the treatmentof cancer in the present invention. Examples of such agents can be foundin Cancer Principles and Practice of Oncology by V. T. Devita and S.Hellman (editors), 6^(th) edition (Feb. 15, 2001), Lippincott Williams &Wilkins Publishers. A person of ordinary skill in the art would be ableto discern which combinations of agents would be useful based on theparticular characteristics of the drugs and the cancer involved. Typicalanti-neoplastic agents useful in the present invention include, but arenot limited to, anti-microtubule agents such as diterpenoids and vincaalkaloids; platinum coordination complexes; alkylating agents such asnitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, andtriazenes; antibiotic agents such as anthracyclins, actinomycins andbleomycins; topoisomerase II inhibitors such as epipodophyllotoxins;antimetabolites such as purine and pyrimidine analogues and anti-folatecompounds; topoisomerase I inhibitors such as camptothecins; hormonesand hormonal analogues; signal transduction pathway inhibitors;non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeuticagents; proapoptotic agents; cell cycle signaling inhibitors; proteasomeinhibitors; and inhibitors of cancer metabolism.

Examples of a further active agent or agents (anti-neoplastic agent) foruse in combination or co-administered with a presently inventedpharmaceutical dosage form, are chemotherapeutic agents.

Anti-microtubule or anti-mitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Examples of anti-microtubule agents include, but are notlimited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specificanti-cancer agents that operate at the G₂/M phases of the cell cycle. Itis believed that the diterpenoids stabilize the β-tubulin subunit of themicrotubules, by binding with this protein. Disassembly of the proteinappears then to be inhibited with mitosis being arrested and cell deathfollowing. Examples of diterpenoids include, but are not limited to,paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate 13-ester with(2R,3S)—N-benzoyl-3-phenylisoserine; is a natural diterpene productisolated from the Pacific yew tree Taxus brevifolia and is commerciallyavailable as an injectable solution TAXOL®. It is a member of the taxanefamily of terpenes. It was first isolated in 1971 by Wani et al. J. Am.Chem., Soc., 93:2325. 1971), who characterized its structure by chemicaland X-ray crystallographic methods. One mechanism for its activityrelates to paclitaxel's capacity to bind tubulin, thereby inhibitingcancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA,77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar,J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis andanticancer activity of some paclitaxel derivatives see: D. G. I.Kingston et al., Studies in Organic Chemistry vol. 26, entitled “Newtrends in Natural Products Chemistry 1986”, Attaur-Rahman, P. W. LeQuesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical use in the treatment ofrefractory ovarian cancer in the United States (Markman et al., YaleJournal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann.Intern, Med., 111:273, 1989) and for the treatment of breast cancer(Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potentialcandidate for treatment of neoplasms in the skin (Einzig et. al., Proc.Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastireet. al., Sem. Oncol., 20:56, 1990). The compound also shows potentialfor the treatment of polycystic kidney disease (Woo et. al., Nature,368:750. 1994), lung cancer and malaria. Treatment of patients withpaclitaxel results in bone marrow suppression (multiple cell lineages,Ignoff, R. J. et. al, Cancer Chemotherapy Pocket Guide, 1998) related tothe duration of dosing above a threshold concentration (50 nM) (Kearns,C. M. et. al., Seminars in Oncology, 3(6) p. 16-23, 1995).

Docetaxel, (2R,3S)—N-carboxy-3-phenylisoserine, N-tert-butyl ester,13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate, trihydrate; is commercially available as aninjectable solution as TAXOTERE®. Docetaxel is indicated for thetreatment of breast cancer. Docetaxel is a semisynthetic derivative ofpaclitaxel q.v., prepared using a natural precursor,10-deacetyl-baccatin III, extracted from the needle of the European Yewtree. The dose limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived fromthe periwinkle plant. Vinca alkaloids act at the M phase (mitosis) ofthe cell cycle by binding specifically to tubulin. Consequently, thebound tubulin molecule is unable to polymerize into microtubules.Mitosis is believed to be arrested in metaphase with cell deathfollowing. Examples of vinca alkaloids include, but are not limited to,vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available asVELBAN® as an injectable solution. Although, it has possible indicationas a second line therapy of various solid tumors, it is primarilyindicated in the treatment of testicular cancer and various lymphomasincluding Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commerciallyavailable as ONCOVIN® as an injectable solution. Vincristine isindicated for the treatment of acute leukemias and has also found use intreatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.Alopecia and neurologic effects are the most common side effect ofvincristine and to a lesser extent myelosupression and gastrointestinalmucositis effects occur.

Vinorelbine,3′,4′-didehydro-4′-deoxy-C′-norvincaleukoblastine[R—(R*,R*)-2,3-dihydroxybutanedioate(1:2)(salt)], commercially available as an injectable solution ofvinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.Vinorelbine is indicated as a single agent or in combination with otherchemotherapeutic agents, such as cisplatin, in the treatment of varioussolid tumors, particularly non-small cell lung, advanced breast, andhormone refractory prostate cancers. Myelosuppression is the most commondose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-canceragents, which are interactive with DNA. The platinum complexes entertumor cells, undergo, aquation and form intra- and interstrandcrosslinks with DNA causing adverse biological effects to the tumor.Examples of platinum coordination complexes include, but are not limitedto, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available asPLATINOL® as an injectable solution. Cisplatin is primarily indicated inthe treatment of metastatic testicular and ovarian cancer and advancedbladder cancer. The primary dose limiting side effects of cisplatin arenephrotoxicity, which may be controlled by hydration and diuresis, andototoxicity.

Carboplatin, platinum, diammine[1,1-cyclobutane-dicarboxylate(2-)-O,O′],is commercially available as PARAPLATIN® as an injectable solution.Carboplatin is primarily indicated in the first and second linetreatment of advanced ovarian carcinoma. Bone marrow suppression is thedose limiting toxicity of carboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strongelectrophiles. Typically, alkylating agents form covalent linkages, byalkylation, to DNA through nucleophilic moieties of the DNA moleculesuch as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazolegroups. Such alkylation disrupts nucleic acid function leading to celldeath. Examples of alkylating agents include, but are not limited to,nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil;alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; andtriazenes such as dacarbazine.

Cyclophosphamide,2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemonohydrate, is commercially available as an injectable solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent orin combination with other chemotherapeutic agents, in the treatment ofmalignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea,vomiting and leukopenia are the most common dose limiting side effectsof cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commerciallyavailable as an injectable solution or tablets as ALKERAN®. Melphalan isindicated for the palliative treatment of multiple myeloma andnon-resectable epithelial carcinoma of the ovary. Bone marrowsuppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, iscommercially available as LEUKERAN® tablets. Chlorambucil is indicatedfor the palliative treatment of chronic lymphatic leukemia, andmalignant lymphomas such as lymphosarcoma, giant follicular lymphoma,and Hodgkin's disease. Bone marrow suppression is the most common doselimiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially availableas MYLERAN® TABLETS. Busulfan is indicated for the palliative treatmentof chronic myelogenous leukemia. Bone marrow suppression is the mostcommon dose limiting side effects of busulfan.

Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commerciallyavailable as single vials of lyophilized material as BiCNU®. Carmustineis indicated for the palliative treatment as a single agent or incombination with other agents for brain tumors, multiple myeloma,Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppressionis the most common dose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, iscommercially available as single vials of material as DTIC-Dome®.Dacarbazine is indicated for the treatment of metastatic malignantmelanoma and in combination with other agents for the second linetreatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are themost common dose limiting side effects of dacarbazine.

Antibiotic anti-neoplastics are non-phase specific agents, which bind orintercalate with DNA. Typically, such action results in stable DNAcomplexes or strand breakage, which disrupts ordinary function of thenucleic acids leading to cell death. Examples of antibioticanti-neoplastic agents include, but are not limited to, actinomycinssuch as dactinomycin, anthrocyclins such as daunorubicin anddoxorubicin; and bleomycins.

Dactinomycin, also know as Actinomycin D, is commercially available ininjectable form as COSMEGEN®. Dactinomycin is indicated for thetreatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, andanorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin,(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione hydrochloride, is commercially available as a liposomalinjectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.Daunorubicin is indicated for remission induction in the treatment ofacute nonlymphocytic leukemia and advanced HIV associated Kaposi'ssarcoma. Myelosuppression is the most common dose limiting side effectof daunorubicin.

Doxorubicin,(8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedionehydrochloride, is commercially available as an injectable form as RUBEX®or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatmentof acute lymphoblastic leukemia and acute myeloblastic leukemia, but isalso a useful component in the treatment of some solid tumors andlymphomas. Myelosuppression is the most common dose limiting side effectof doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated froma strain of Streptomyces verticillus, is commercially available asBLENOXANE®. Bleomycin is indicated as a palliative treatment, as asingle agent or in combination with other agents, of squamous cellcarcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneoustoxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to,epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derivedfrom the mandrake plant. Epipodophyllotoxins typically affect cells inthe S and G₂ phases of the cell cycle by forming a ternary complex withtopoisomerase II and DNA causing DNA strand breaks. The strand breaksaccumulate and cell death follows. Examples of epipodophyllotoxinsinclude, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially availableas an injectable solution or capsules as VePESID® and is commonly knownas VP-16. Etoposide is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of testicular andnon-small cell lung cancers. Myelosuppression is the most common sideeffect of etoposide. The incidence of leucopenia tends to be more severethan thrombocytopenia.

Teniposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially availableas an injectable solution as VUMON® and is commonly known as VM-26.Teniposide is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia in children.Myelosuppression is the most common dose limiting side effect ofteniposide. Teniposide can induce both leucopenia and thrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. Consequently, S phase doesnot proceed and cell death follows. Examples of antimetaboliteanti-neoplastic agents include, but are not limited to, fluorouracil,methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4-(1H,3H) pyrimidinedione, is commerciallyavailable as fluorouracil. Administration of 5-fluorouracil leads toinhibition of thymidylate synthesis and is also incorporated into bothRNA and DNA. The result typically is cell death. 5-fluorouracil isindicated as a single agent or in combination with other chemotherapyagents in the treatment of carcinomas of the breast, colon, rectum,stomach and pancreas. Myelosuppression and mucositis are dose limitingside effects of 5-fluorouracil. Other fluoropyrimidine analogs include5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridinemonophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (1H)-pyrimidinone, iscommercially available as CYTOSAR-U® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phaseby inhibiting DNA chain elongation by terminal incorporation ofcytarabine into the growing DNA chain. Cytarabine is indicated as asingle agent or in combination with other chemotherapy agents in thetreatment of acute leukemia. Other cytidine analogs include5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine). Cytarabineinduces leucopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, iscommercially available as PURINETHOL®. Mercaptopurine exhibits cellphase specificity at S-phase by inhibiting DNA synthesis by an as of yetunspecified mechanism. Mercaptopurine is indicated as a single agent orin combination with other chemotherapy agents in the treatment of acuteleukemia. Myelosuppression and gastrointestinal mucositis are expectedside effects of mercaptopurine at high doses. A useful mercaptopurineanalog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commerciallyavailable as TABLOID®. Thioguanine exhibits cell phase specificity atS-phase by inhibiting DNA synthesis by an as of yet unspecifiedmechanism. Thioguanine is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of acute leukemia.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of thioguanine administration.However, gastrointestinal side effects occur and can be dose limiting.Other purine analogs include pentostatin, erythrohydroxynonyladenine,fludarabine phosphate, and cladribine.

Gemcitabine, 2′-deoxy-2′,2′-difluorocytidine monohydrochloride(β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibitscell phase specificity at S-phase and by blocking progression of cellsthrough the G1/S boundary. Gemcitabine is indicated in combination withcisplatin in the treatment of locally advanced non-small cell lungcancer and alone in the treatment of locally advanced pancreatic cancer.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of gemcitabine administration.

Methotrexate,N-[4[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamicacid, is commercially available as methotrexate sodium. Methotrexateexhibits cell phase effects specifically at S-phase by inhibiting DNAsynthesis, repair and/or replication through the inhibition ofdyhydrofolic acid reductase which is required for synthesis of purinenucleotides and thymidylate. Methotrexate is indicated as a single agentor in combination with other chemotherapy agents in the treatment ofchoriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, andcarcinomas of the breast, head, neck, ovary and bladder.Myelosuppression (leucopenia, thrombocytopenia, and anemia) andmucositis are expected side effect of methotrexate administration.

Camptothecins, including, camptothecin and camptothecin derivatives areavailable or under development as Topoisomerase I inhibitors.Camptothecins cytotoxic activity is believed to be related to itsTopoisomerase I inhibitory activity. Examples of camptothecins include,but are not limited to irinotecan, topotecan, and the various opticalforms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecindescribed below.

Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride, is commercially available as the injectable solutionCAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with itsactive metabolite SN-38, to the topoisomerase I-DNA complex. It isbelieved that cytotoxicity occurs as a result of irreparable doublestrand breaks caused by interaction of the topoisomerase I:DNA:irintecanor SN-38 ternary complex with replication enzymes. Irinotecan isindicated for treatment of metastatic cancer of the colon or rectum. Thedose limiting side effects of irinotecan HCl are myelosuppression,including neutropenia, and GI effects, including diarrhea.

Topotecan HCl,(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dionemonohydrochloride, is commercially available as the injectable solutionHYCAMTIN®. Topotecan is a derivative of camptothecin which binds to thetopoisomerase I-DNA complex and prevents religation of singles strandbreaks caused by Topoisomerase I in response to torsional strain of theDNA molecule. Topotecan is indicated for second line treatment ofmetastatic carcinoma of the ovary and small cell lung cancer. The doselimiting side effect of topotecan HCl is myelosuppression, primarilyneutropenia.

Also of interest, is the camptothecin derivative of Formula A following,including the racemic mixture (R,S) form as well as the R and Senantiomers:

known by the chemical name“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R,S)-camptothecin(racemic mixture) or“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R)-camptothecin(R enantiomer) or“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(S)-camptothecin(S enantiomer). Such compound as well as related compounds aredescribed, including methods of making, in U.S. Pat. Nos. 6,063,923;5,342,947; 5,559,235; 5,491,237 and pending U.S. patent application Ser.No. 08/977,217 filed Nov. 24, 1997.

Hormones and hormonal analogues are useful compounds for treatingcancers in which there is a relationship between the hormone(s) andgrowth and/or lack of growth of the cancer. Examples of hormones andhormonal analogues useful in cancer treatment include, but are notlimited to, adrenocorticosteroids such as prednisone and prednisolonewhich are useful in the treatment of malignant lymphoma and acuteleukemia in children; aminoglutethimide and other aromatase inhibitorssuch as anastrozole, letrazole, vorazole, and exemestane useful in thetreatment of adrenocortical carcinoma and hormone dependent breastcarcinoma containing estrogen receptors; progestrins such as megestrolacetate useful in the treatment of hormone dependent breast cancer andendometrial carcinoma; estrogens, androgens, and anti-androgens such asflutamide, nilutamide, bicalutamide, cyproterone acetate and5α-reductases such as finasteride and dutasteride, useful in thetreatment of prostatic carcinoma and benign prostatic hypertrophy;anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene,iodoxyfene, as well as selective estrogen receptor modulators (SERMS)such those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and6,207,716, useful in the treatment of hormone dependent breast carcinomaand other susceptible cancers; and gonadotropin-releasing hormone (GnRH)and analogues thereof which stimulate the release of leutinizing hormone(LH) and/or follicle stimulating hormone (FSH) for the treatmentprostatic carcinoma, for instance, LHRH agonists and antagagonists suchas goserelin acetate and luprolide.

Signal transduction pathway inhibitors are those inhibitors, which blockor inhibit a chemical process which evokes an intracellular change. Asused herein this change is cell proliferation or differentiation. Signaltranduction inhibitors useful in the present invention includeinhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases,SH2/SH3 domain blockers, serine/threonine kinases,phosphotidylinositol-3 kinases, myo-inositol signaling, and Rasoncogenes.

Several protein tyrosine kinases catalyse the phosphorylation ofspecific tyrosyl residues in various proteins involved in the regulationof cell growth. Such protein tyrosine kinases can be broadly classifiedas receptor or non-receptor kinases.

Receptor tyrosine kinases are transmembrane proteins having anextracellular ligand binding domain, a transmembrane domain, and atyrosine kinase domain. Receptor tyrosine kinases are involved in theregulation of cell growth and are generally termed growth factorreceptors. Inappropriate or uncontrolled activation of many of thesekinases, i.e. aberrant kinase growth factor receptor activity, forexample by over-expression or mutation, has been shown to result inuncontrolled cell growth. Accordingly, the aberrant activity of suchkinases has been linked to malignant tissue growth. Consequently,inhibitors of such kinases could provide cancer treatment methods.Growth factor receptors include, for example, epidermal growth factorreceptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2,erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosinekinase with immunoglobulin-like and epidermal growth factor homologydomains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophagecolony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growthfactor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin(eph) receptors, and the RET protooncogene. Several inhibitors of growthreceptors are under development and include ligand antagonists,antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.Growth factor receptors and agents that inhibit growth factor receptorfunction are described, for instance, in Kath, John C., Exp. Opin. Ther.Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 Feb. 1997;and Lofts, F. J. et al, “Growth factor receptors as targets”, NewMolecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr,David, CRC press 1994, London.

Tyrosine kinases, which are not growth factor receptor kinases aretermed non-receptor tyrosine kinases. Non-receptor tyrosine kinases foruse in the present invention, which are targets or potential targets ofanti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focaladhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Suchnon-receptor kinases and agents which inhibit non-receptor tyrosinekinase function are described in Sinh, S, and Corey, S. J., (1999)Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; andBolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15:371-404.

SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domainbinding in a variety of enzymes or adaptor proteins including, PI3-K p85subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) andRas-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussedin Smithgall, T. E. (1995), Journal of Pharmacological and ToxicologicalMethods. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascadeblockers which include blockers of Raf kinases (rafk), Mitogen orExtracellular Regulated Kinase (MEKs), and Extracellular RegulatedKinases (ERKs); and Protein kinase C family member blockers includingblockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase familymembers, PDK1 and TGF beta receptor kinases. Such Serine/Threoninekinases and inhibitors thereof are described in Yamamoto, T., Taya, S.,Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt,P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60.1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys.27:41-64; Philip, P. A., and Harris, A. L. (1995), Cancer Treatment andResearch. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal ChemistryLetters, (10), 2000, 223-226; U.S. Pat. No. 6,268,391; Pearce, L. R etal. Nature Reviews Molecular Cell Biology (2010) 11, 9-22. andMartinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.

Suitably, the pharmaceutically active compound of the invention is usedin combination with a B-Raf inhibitor. Suitably,N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide,or a pharmaceutically acceptable salt thereof, which is disclosed andclaimed, in International Application No. PCT/US2009/042682, having anInternational filing date of May 4, 2009, the entire disclosure of whichis hereby incorporated by reference.N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamidecan be prepared as described in International Application No.PCT/US2009/042682.

Suitably, the pharmaceutically active compound of the invention is usedin combination with an Akt inhibitor. Suitably,N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamideor a pharmaceutically acceptable salt thereof, which is disclosed andclaimed in International Application No. PCT/US2008/053269, having anInternational filing date of Feb. 7, 2008; International PublicationNumber WO 2008/098104 and an International Publication date of Aug. 14,2008, the entire disclosure of which is hereby incorporated byreference.N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamideis the compound of example 224 and can be prepared as described inInternational Application No. PCT/US2008/053269.

Suitably, the pharmaceutically active compound of the invention is usedin combination with an Akt inhibitor. Suitably,N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamideor a pharmaceutically acceptable salt thereof, which is disclosed andclaimed in International Application No. PCT/US2008/053269, having anInternational filing date of Feb. 7, 2008; International PublicationNumber WO 2008/098104 and an International Publication date of Aug. 14,2008, the entire disclosure of which is hereby incorporated byreference.N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamideis the compound of example 96 and can be prepared as described inInternational Application No. PCT/US2008/053269. Suitably,N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamideis in the form of a hydrochloride salt. The salt form can be prepared byone of skill in the art from the description in InternationalApplication No. PCT/US2010/022323, having an International filing dateof Jan. 28, 2010.

Inhibitors of Phosphotidylinositol-3 Kinase family members includingblockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in thepresent invention. Such kinases are discussed in Abraham, R. T. (1996),Current Opinion in Immunology. 8 (3) 412-8; Canman, C. E., Lim, D. S.(1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), InternationalJournal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. etal, Cancer res, (2000) 60(6), 1541-1545.

Also of interest in the present invention are Myo-inositol signalinginhibitors such as phospholipase C blockers and Myoinositol analogues.Such signal inhibitors are described in Powis, G., and Kozikowski A.,(1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workmanand David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitorsof Ras Oncogene. Such inhibitors include inhibitors offarnesyltransferase, geranyl-geranyl transferase, and CAAX proteases aswell as anti-sense oligonucleotides, ribozymes and immunotherapy. Suchinhibitors have been shown to block ras activation in cells containingwild type mutant ras, thereby acting as antiproliferation agents. Rasoncogene inhibition is discussed in Scharovsky, O. G., Rozados, V. R.,Gervasoni, S. I. Matar, P. (2000), Journal of Biomedical Science. 7(4)292-8; Ashby, M. N. (1998), Current Opinion in Lipidology. 9 (2) 99-102;and BioChim. Biophys. Acta, (19899) 1423(3):19-30.

As mentioned above, antibody antagonists to receptor kinase ligandbinding may also serve as signal transduction inhibitors. This group ofsignal transduction pathway inhibitors includes the use of humanizedantibodies to the extracellular ligand binding domain of receptortyrosine kinases. For example Imclone C225 EGFR specific antibody (seeGreen, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, CancerTreat. Rev., (2000), 26(4), 269-286); Herceptin® erbB2 antibody (seeTyrosine Kinase Signalling in Breast cancer:erbB Family ReceptorTyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CBVEGFR2 specific antibody (see Brekken, R. A. et al, Selective Inhibitionof VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumorgrowth in mice, Cancer Res. (2000) 60, 5117-5124).

Non-receptor kinase angiogenesis inhibitors may also be useful in thepresent invention. Inhibitors of angiogenesis related VEGFR and TIE2 arediscussed above in regard to signal transduction inhibitors (bothreceptors are receptor tyrosine kinases). Angiogenesis in general islinked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR havebeen shown to inhibit angiogenesis, primarily VEGF expression.Accordingly, non-receptor tyrosine kinase inhibitors may be used incombination with the compounds of the present invention. For example,anti-VEGF antibodies, which do not recognize VEGFR (the receptortyrosine kinase), but bind to the ligand; small molecule inhibitors ofintegrin (alpha_(v) beta₃) that will inhibit angiogenesis; endostatinand angiostatin (non-RTK) may also prove useful in combination with thedisclosed compounds. (See Bruns C J et al (2000), Cancer Res., 60:2926-2935; Schreiber A B, Winkler M E, and Derynck R. (1986), Science,232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).

Agents used in immunotherapeutic regimens may also be useful incombination with the compounds of Formula (I). There are a number ofimmunologic strategies to generate an immune response. These strategiesare generally in the realm of tumor vaccinations. The efficacy ofimmunologic approaches may be greatly enhanced through combinedinhibition of signaling pathways using a small molecule inhibitor.Discussion of the immunologic/tumor vaccine approach against erbB2/EGFRare found in Reilly R T et al. (2000), Cancer Res. 60: 3569-3576; andChen Y, Hu D, Eling D J, Robbins J, and Kipps T J. (1998), Cancer Res.58: 1965-1971.

Agents used in proapoptotic regimens (e.g., bcl-2 antisenseoligonucleotides) may also be used in the combination of the presentinvention. Members of the Bcl-2 family of proteins block apoptosis.Upregulation of bcl-2 has therefore been linked to chemoresistance.Studies have shown that the epidermal growth factor (EGF) stimulatesanti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore,strategies designed to downregulate the expression of bcl-2 in tumorshave demonstrated clinical benefit and are now in Phase II/III trials,namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptoticstrategies using the antisense oligonucleotide strategy for bcl-2 arediscussed in Water J S et al. (2000), J. Clin. Oncol. 18: 1812-1823; andKitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

Cell cycle signalling inhibitors inhibit molecules involved in thecontrol of the cell cycle. A family of protein kinases called cyclindependent kinases (CDKs) and their interaction with a family of proteinstermed cyclins controls progression through the eukaryotic cell cycle.The coordinate activation and inactivation of different cyclin/CDKcomplexes is necessary for normal progression through the cell cycle.Several inhibitors of cell cycle signalling are under development. Forinstance, examples of cyclin dependent kinases, including CDK2, CDK4,and CDK6 and inhibitors for the same are described in, for instance,Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. Further,p21WAF1/CIP1 has been described as a potent and universal inhibitor ofcyclin-dependent kinases (Cdks) (Ball et al., Progress in Cell CycleRes., 3: 125 (1997)). Compounds that are known to induce expression ofp21WAF1/CIP1 have been implicated in the suppression of cellproliferation and as having tumor suppressing activity (Richon et al.,Proc. Nat Acad. Sci. U.S.A. 97(18): 10014-10019 (2000)), and areincluded as cell cycle signaling inhibitors. Histone deacetylase (HDAC)inhibitors are implicated in the transcriptional activation ofp21WAF1/CIP1 (Vigushin et al., Anticancer Drugs, 13(1): 1-13 (January2002)), and are suitable cell cycle signaling inhibitors for use herein.Examples of such HDAC inhibitors include:

1. Vorinostat, including pharmaceutically acceptable salts thereof.Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger,Community Oncology 4, 384-386 (2007).

Vorinostat has the following chemical structure and name:

N-hydroxy-N′-phenyl-octanediamide

2. Romidepsin, including pharmaceutically acceptable salts thereof.Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93.

Romidepsin, has the following chemical structure and name:

(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone

3. Panobinostat, including pharmaceutically acceptable salts thereof.Drugs of the Future 32(4): 315-322 (2007).

Panobinostat, has the following chemical structure and name:

(2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

4. Valproic acid, including pharmaceutically acceptable salts thereof.Gottlicher, et al., EMBO J. 20(24): 6969-6978 (2001).

Valproic acid, has the following chemical structure and name:

2-propylpentanoic acid

5. Mocetinostat (MGCD0103), including pharmaceutically acceptable saltsthereof. Balasubramanian et al., Cancer Letters 280: 211-221 (2009).

Mocetinostat, has the following chemical structure and name:

N-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl]benzamide

Further examples of such HDAC inhibitors are included in BertrandEuropean Journal of Medicinal Chemistry 45, (2010) 2095-2116,particularly the compounds of table 3 therein as indicated below.

Proteasome inhibitors are drugs that block the action of proteasomes,cellular complexes that break down proteins, like the p53 protein.Several proteasome inhibitors are marketed or are being studied in thetreatment of cancer. Suitable proteasome inhibitors for use hereininclude:

1. Bortezomib (Velcade®), including pharmaceutically acceptable saltsthereof. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-11.

Bortezomib has the following chemical structure and name.

[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronicacid

2. Disulfuram, including pharmaceutically acceptable salts thereof.Bouma et al. (1998). J. Antimicrob. Chemother. 42 (6): 817-20.

Disulfuram has the following chemical structure and name.

1,1′,1″,1″′-[disulfanediylbis(carbonothioylnitrilo)]tetraethane

3. Epigallocatechin gallate (EGCG), including pharmaceuticallyacceptable salts thereof. Williamson et al., (December 2006), TheJournal of Allergy and Clinical Immunology 118 (6): 1369-74.

Epigallocatechin gallate has the following chemical structure and name.

[(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl]3,4,5-trihydroxybenzoate

4. Salinosporamide A, including pharmaceutically acceptable saltsthereof. Feling et at., (2003), Angew. Chem. Int. Ed. Engl. 42 (3):355-7.

Salinosporamide A has the following chemical structure and name.

(4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclohex-2-enyl(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo3.2.0heptane-3,7-dione

Inhibitors of cancer metabolism—Many tumor cells show a markedlydifferent metabolism from that of normal tissues. For example, the rateof glycolysis, the metabolic process that converts glucose to pyruvate,is increased, and the pyruvate generated is reduced to lactate, ratherthan being further oxidized in the mitochondria via the tricarboxylicacid (TCA) cycle. This effect is often seen even under aerobicconditions and is known as the Warburg Effect.

Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenaseexpressed in muscle cells, plays a pivotal role in tumor cell metabolismby performing the reduction of pyruvate to lactate, which can then beexported out of the cell. The enzyme has been shown to be upregulated inmany tumor types. The alteration of glucose metabolism described in theWarburg effect is critical for growth and proliferation of cancer cellsand knocking down LDH-A using RNA-i has been shown to lead to areduction in cell proliferation and tumor growth in xenograft models.

-   D. A. Tennant et. al., Nature Reviews, 2010, 267.-   P. Leder, et. al., Cancer Cell, 2006, 9, 425.

Inhibitors of cancer metabolism, including inhibitors of LDH-A, aresuitable for use in combination with the compounds of this invention.

By the term “dry blend” and derivatives thereof, as used herein refersto formulated particles that comprise Compound A and/or diluents and/orbinders and/or lubricants and/or disintegrants such that the particlesare suitable for utilization in preparing solid oral pharmaceuticaldosage forms, suitably tablets, suitably capsules and are produced bydry blending or dry granulation. It is possible to administer the dryblend directly to a subject in need thereof as a medicament. However, itis anticipated that the dry blend are most appropriately utilized in thepreparation of solid oral pharmaceutical dosage forms, suitably tablets,suitably capsules, as indicated above.

By the term “solid oral pharmaceutical dosage form” and “solid dosageform” and derivatives thereof, as used herein, unless otherwise defined,refers to a final pharmaceutical preparation that comprises Compound A,such as: tablets, capsules, pellets, lozenges, sachets and powders(including coated versions of any of such preparations), suitablytablets, suitably capsules, that are suitable for in vivoadministration.

When indicating that an excipient for use herein is substantially freeof water, it is contemplated that the excipient could contain minoramounts of water, for example: about 5% by weight or less, suitablyabout 2.5% by weight of less, suitably about 1% by weight of less. Inthis aspect of the invention, it is believed that very minor amounts ofwater can be in the excipient component without adversely affecting theperformance of the solid dosage from, suitably the tablet, suitably thecapsule.

Suitably, the solid oral pharmaceutical dosage forms of the presentinvention comprise Compound A, a diluent (also known as filler orbulking agent), and suitably also a binder and/or a lubricant and/or adisintegrant. Those skilled in the art will recognize that a givenmaterial may provide one or more functions in the tablet formulation,although the material is usually included for a primary function. Thepercentages of diluent, binder, lubricant and disintegrant providedherein and in the claims are by weight of the tablet.

Diluents provide bulk, for example, in order to make the tablet apractical size for processing. Diluents may also aid processing, forexample, by providing improved physical properties such as flow,compressibility, and tablet hardness. Because of the relatively highpercentage of diluent and the amount of direct contact between thediluent and the active compound in the typical pharmaceuticalformulation, the interaction of the diluent with the active compound isof particular concern to the formulator. Examples of diluents suitablefor use in the present invention include either the following or ananhydrous version thereof: water-soluble fillers and water-insolublefillers, such as calcium phosphate (e.g., di and tri basic, hydrated oranhydrous), calcium sulfate, calcium carbonate, magnesium carbonate,kaolin, lactose that is substantially free of water, suitably spraydried or anhydrous lactose (collectively lactose as used herein),cellulose (e.g., microcrystalline cellulose, powdered cellulose),pregelatinized starch, starch, lactitol, mannitol, sorbitol,maltodextrin, powdered sugar, compressible sugar, sucrose, dextrose, andinositol. Diluents that are substantially free of water are suitable fortablets of the current invention. In one embodiment of the presentinvention, the diluent is composed of one or both of Mannitol andmicrocrystalline cellulose.

The solid oral pharmaceutical dosage forms of the present inventiontypically comprise from about 25% to about 89%, of one or more diluents.

One aspect of the present invention comprises solid oral pharmaceuticaldosage forms wherein the solid dosage forms are formulated using adiluent or diluents that are substantially free of water.

One aspect of the present invention comprises pharmaceutical tablets,wherein the tablets are formulated using a diluent or diluents that aresubstantially free of water.

One aspect of the present invention comprises pharmaceutical capsules,wherein the capsules are formulated using a diluent or diluents that aresubstantially free of water.

Binders impart cohesive properties to the powdered material. Examples ofbinders suitable for use in the present invention include either thefollowing or an anhydrous version thereof: hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose(HEC) and ethyl cellulose (EC)], polyvinylpyrrolidone. Binders that aresubstantially free of water are suitable for tablets of the currentinvention. In one embodiment of the present invention, the binder ishydroxypropyl methyl cellulose (HPMC) or Hypromellose.

The solid oral pharmaceutical dosage forms of the present inventiontypically comprise up to about 2-8% binder such as about 2%, about 3%,about 4%, about 5%, about 6% about 7%, and about 8% w/w. Theformulations suitably comprise up to about 5% binder.

One aspect of the present invention comprises solid oral pharmaceuticaldosage forms wherein the solid dosage forms are formulated using abinder or binders that are substantially free of water.

One aspect of the present invention comprises pharmaceutical tablets,wherein the tablets are formulated using a binder or binders that aresubstantially free of water.

One aspect of the present invention comprises pharmaceutical capsules,wherein the capsules are formulated using a binder or binders that aresubstantially free of water.

Lubricants are generally used to enhance processing, for example, toprevent adhesion of the formulation material to manufacturing equipment,reduce interparticle friction, improve rate of flow of the formulation,and/or assist ejection of the formulations from the manufacturingequipment. Examples of lubricants suitable for use in the presentinvention include either the following or an anhydrous version thereof:talc, stearates (e.g., magnesium stearate, calcium stearate, zincstearate, palmitostearate), stearic acid, hydrogenated vegetable oils,glyceryl behanate, polyethylene glycol, ethylene oxide polymers (e.g.,CARBOWAXes), liquid paraffin, sodium lauryl sulfate, magnesium laurylsulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, and silicaderivatives (e.g., colloidal silicon dioxide, colloidal silica,pyrogenic silica, and sodium silicoaluminate). Lubricants that aresubstantially free of water are suitable for tablets of the currentinvention. In one embodiment of the present invention, the lubricant ismagnesium stearate.

The solid oral pharmaceutical dosage forms of the present inventiontypically comprise up to about 2% lubricant. The formulations suitablycomprise up to about 1%, suitably up to about 0.75% lubricant.

One aspect of the present invention comprises solid oral pharmaceuticaldosage forms wherein the solid dosage forms are formulated using alubricant or lubricants that are substantially free of water.

One aspect of the present invention comprises pharmaceutical tablets,wherein the tablets are formulated using a lubricant or lubricants thatare substantially free of water.

One aspect of the present invention comprises pharmaceutical capsules,wherein the capsules are formulated using a lubricant or lubricants thatare substantially free of water.

Disintegrants are employed to facilitate breakup or disintegration ofthe formulation after administration. Examples of disintegrants suitablefor use in the present invention include either the following or ananhydrous version thereof: starches, celluloses, gums, crosslinkedpolymers, and effervescent agents, such as corn starch, potato starch,pregelatinized starch, modified corn starch, croscarmellose sodium,crospovidone, sodium starch glycolate, Veegum HV, methyl cellulose,microcrystalline cellulose, cellulose, colloidal silicon dioxide,modified cellulose gum (e.g., Ac-Di-Sol R), agar, bentonite,montmorillonite clay, natural sponge, cation exchange resins, ionexchange resins (e.g., polyacrin potassium), alginic acid and alginates,guar gum, citrus pulp, carboxymethylcellulose and salts thereof such assodium lauryl sulfate, magnesium aluminum silicate, hydrous aluminumsilicate, sodium bicarbonate in admixture with an acidulant such astartaric acid or citric acid. Disintegrants that are substantially freeof water are suitable for tablets of the current invention. In oneembodiment of the present invention, the disintegrant is composed of oneor more of: croscarmellose sodium, sodium lauryl sulfate and colloidalsilicon dioxide.

The solid oral pharmaceutical dosage forms of the present inventiontypically comprise an amount from 2% to about 5% disintegrant, suitablyabout 2%, about 3%, about 4%, and about 5% w/w. The formulationssuitably comprise about 3% disintegrant.

One aspect of the present invention comprises solid oral pharmaceuticaldosage forms wherein the solid dosage forms are formulated using adisintegrant or disintegrants that are substantially free of water.

One aspect of the present invention comprises pharmaceutical tablets,wherein the tablets are formulated using a disintegrant or disintegrantsthat are substantially free of water.

One aspect of the present invention comprises pharmaceutical capsules,wherein the capsules are formulated using a disintegrant ordisintegrants that are substantially free of water.

When administered in vivo, each pharmaceutical compound acts uniquely inregards to therapeutic drug levels. Further, pharmaceutically activecompounds are often associated with undesirable side effects such as;toxicity (e.g. genotoxicity, teratogenicity) and undesirable physical orpsychological manifestations. In addition to balancing the drug'schemical properties with those of the excipients, the drug must beadministered at a specific amount that is sufficient to provide thedesired therapeutic drug level but less than the amount that presents anunacceptable side effect profile, or within a therapeutic window forthat particular drug. One embodiment of this invention is directed toadministering Compound A in an amount sufficient to provide the desiredtherapeutic effect and an acceptable side effect profile.

Dosing Strength

Numerous studies usingN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidewere conducted in animal models in an attempt to establish a doseselection range for human studies. The animal models included thefollowing.

Pharmacokinetics and Metabolism in Animals

The pharmacokinetics, absorption, distribution, metabolism andelimination ofN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamideand solvates thereof, including the dimethyl sulfoxide solvate(collectively referred to as “Compound” when used in connection withanimal models or human clinical trials), were investigated in a seriesof in vitro investigations and with in vivo oral (gavage) and IV studiesin the Balb/c mouse, Sprague Dawley rat (unless otherwise stated),beagle dog and cynomolgus monkey using unlabeled and [14C]-labeledCompound. A list of these studies is included, along with subsequentlyobtained human clinical results, in Table 1 below. For in vivo studies,various formulations were used. For oral dosing, solutions orsuspensions were administered. Further, some pharmacokinetic andtoxicity studies utilized micronized Compound, including the 13 weektoxicity studies in rats and dogs.

TABLE 1 List of Pharmacokinetic and Product Metabolism Studies with“Compound” Type of Study Route Dose (mg/kg) [mg/m²] Form SpeciesNo./Group Single Dose IV or Oral 0.3 to 3 A/B/H^(SOL) Mouse 3F IV orOral 0.3 to 10 A/B/H^(SOL) Rat 3M IV or Oral 0.3 A/H^(SOL) Dog 3M IV orOral 0.3 B Monkey 3M Dose escalation Oral 3, 10, 30, 100 H^(SOL) Rat 3M[24, 80, 240, 800] Dose escalation Oral 0.013 to 3 [0.25 to 60] B Dog1M/1F Repeat Dose Toxicokinetics up to 13 weeks Oral [0.125 up to 24] BRat Up to 18M/F up to 13 weeks Oral [0.1510] B Dog up to 6M/6FDistribution Plasma protein binding In vitro 5 μM A nonclin species NABlood cell association 0.5, 5 μg/mL Human Pgp substrate and passive Invitro up to 5 μM B/[¹⁴C]B Human NA permeability Inhibition ofPgp/OATP1B1/1B3 In vitro up to 50 μM B Human NA BCRP substrate; passiveIn vitro up to 100 μM [¹⁴C]B/B Human NA permeability and inhibitionPermeability in MDCKII-MDR1 In vitro 0.115 to 11.5 μM B Human NA QWBAOral 1 [8] [¹⁴C]B Rat 7M Blood, plasma and liver Oral 1 [8] [¹⁴C]B Rat15M/15F concentrations Blood and plasma concentrations Oral 0.5 [10][¹⁴C]B Dog 3M/3F Metabolism Human blood stability In vitro 5 μg/mL BHuman NA Intrinsic clearance In vitro up to 10 μM A or B nonclinspecies, NA Metabolic stability and profiling Human Oxidative metabolismIn vitro 5 μM [¹⁴C]B Human NA Oxidative bioactivation In vitro 10 μM[¹⁴C]B Human NA Hepatic metabolism In vitro 12.5 μM [¹⁴C]B nonclinspecies, NA Human Hepatic metabolism (IPRL) In situ 30 [¹⁴C]B Rat 5 CYPinhibition (3 studies In vitro 0.01 to 50 μM A or B Human NA conducted)PXR activation In vitro 0.0002 to 10 μM B Rat and Human NA CYP inductionIn vitro 0.01 to 10 μM B Human 3 CYP induction Oral 0.1, 0.3, 1 [0.8,2.4, 8] B Rat 4M Excretion Elimination Oral 1 [8] [¹⁴C]B Rat 3M/3F 3M(BDC) Elimination Oral 0.5 [10] [¹⁴C]B Dog 3M/3F A = Compound (parentform); B = Compound (dimethylsulfoxide solvate); H = Compound (aceticacid solvate); [¹⁴C] = [¹⁴C]-labeled Compound (DMSO solvate); BCRP =Breast cancer resistance protein; BDC = Bile duct cannulated; CYP =Cytochrome P450; HEK = Human embryonic kidney; IV = Intravenous; M =Male; F = Female; NA = Not applicable; MDCKII-MDR1 = Madin-Darby caninekidney type II-multidrug resistance 1; OATP = Organic anion transportingpolypeptide; Pgp = P-glycoprotein; PXR = Pregnane X receptor; QWBA =Quantitative whole body autoradiography; SOL = Solution formulation.NOTE: Oral doses were administered by gavage (using suspensionformulations unless otherwise noted).

Repeat Dose Pharmacokinetics and Toxicology

Comparative systemic exposure (AUC0-t and Cmax) for 13 week studies inrats and dogs are presented in Table 2. Dose range studies in rats atdoses up to 1 mg/kg/day for 14 days and in dogs at doses up to 0.5mg/kg/day (or 10 mg/m2/day) for 10 days were conducted prior to thestudies.

TABLE 2 Comparative Assessment of Mean Systemic Exposure Following OralAdministration of Compound to Rats, Dogs and Humans C_(max) (ng/mL) AUC(ng · h/mL) Species Dose Animal to End of Animal to (Duration)(mg/m²/day) Sex End of Study Human Ratio^(a) Study Human Ratio^(a) Rat0.125 M 1.78 0.08 35.0 0.10 (3 weeks) F 3.33 0.14 60.2 0.17 0.25 M 3.500.15 64.2 0.18 F 6.28 0.27 126 0.35  0.5 (MTD) M 7.78 0.33 129 0.36 F13.0 0.56 211 0.59   1 (MTD) M 13.3 0.57 218 0.61 F 29.4 1.26 460 1.28Rat 0.125 F 5.30 0.23 102 0.28 (13 weeks) 0.25 (MTD) M 5.34 0.23 95.40.27 F 8.03 0.34 158 0.44 0.5 M 15.4^(b) 0.66 277^(b)  0.77 F NC NC NCNC 1.0 M NC NC NC NC Dog 0.3 F 7.19 0.31 120 0.33 (3 weeks) 0.4^(c) F11.6 0.50 211 0.59    0.5 (MTD) ^(c) F 12.3 0.53 205 0.57 M 9.37 0.40159 0.44 0.75^(c) M 19.0^(d) 0.82 282^(d ) 0.78 1.5^(c,e) M NC NC NC NCDog 0.15 M 2.32 0.10 45.6 0.13 (13 weeks) F 2.71 0.12 51.8 0.14 0.3 M5.15 0.22 95.5 0.27 F 7.24 0.31 107 0.30 0.45 (NOAEL) ^(f) M 8.42 0.36128 0.36 F 9.78 0.42 150 0.42 Human 2 mg M&F 23.3 NA 360 NA NA = Notapplicable; NC = Not calculated. Note: Data are the means (n = 3) exceptas noted. Bolded values are maximum tolerated dose (MTD) or No ObservedAdverse Effect Level (NOAEL) as indicated. ^(a)Ratios given with respectto mean human exposures on Day 15 of daily dosing at a dose of 2 mg.^(a)Data obtained from 2 rats. ^(b)Data obtained from 5 dogs. ^(c)Dataobtained from 4 dogs. ^(d)For dogs given 1.5 mg/m²/day, the last day ofdosing was Day 7. ^(e)Dogs received 0.6 mg/m²/day for first 11 to 12days, an approximate 7 day drug holiday and then 0.45 mg/m²/day for theremainder of the study.

In vivo toxicology studies were conducted in Sprague Dawley rats andbeagle dogs by oral gavage (Table 3). Studies were conducted using theDMSO solvate of Compound formulated as a suspension in 1.5%hydroxypropylmethylcellulose, 5% mannitol, and 0.2% sodium laurylsulfate. For all toxicology studies, doses are expressed based on bodysurface area (mg/m2). In general, to convert mg/m2 doses to mg/kg,divide the doses by 8 for rats and 20 for dogs.

TABLE 3 Toxicology Studies Conducted with Compound Type of Study RouteDose [mg/m²] Form Species No./Group Single Dose Dose escalation Oral 24,80, 240, 800 H Rat 3 M Dose escalation Oral 3, 10, 60 B Dog 1 M/F RepeatDose 3 days Oral 2.4, 24, 240 H Rat 5 M 14 days (4 studies conducted)Oral 0.8 to 24 H Rat up to 4M/4F 3 weeks Oral 0.125, 0.25, 0.5, 1 B Rat10 to 16 M/F 13 weeks^(a) Oral M: 0.25, 0.5, 1.0 B Rat 12 to 18 M/F F:0.125, 0.25, 0.5 10 days Oral 2.5, 5, 10 B Dog 1 M/F 3 weeks Oral M:0.5, 0.75, 1.5 B Dog 3 to 5 M/F F: 0.3, 0.4, 0.5 13 weeks^(a) Oral 0.15,0.3, 0.6/0.45 B Dog 4 to 6M/F Genotoxicity Ames In vitro 1.5 to 2500μg/plate B NA NA Mouse lymphoma In vitro 5 to 150 μg/mL B NA NAMicronucleus Oral 7.3, 14.4 B Rat 7M B = Compound (dimethylsulfoxidesolvate); H = Compound (acetic acid solvate); M = Male; F = Female; NA =Not applicable. f. 13 week repeat dose toxicity study followed by a 4week recovery period.

In view of the results observed in animal models, dose range studies forsingle dose and multiple dose human clinical trials were conducted.

Pharmacokinetics, Product Metabolism, and Pharmacodynamics in Humans

Preliminary PK data was obtained in subjects with solid tumors followingsingle- and repeat-dose oral administration of Compound tablets. Thedose-escalation part of the first-time-in-human study (FTIH), involvedadministration of Compound in one of 3 main dosing regimens:

QD dosing with the designated dose for 21 days, followed by 7 dayswithout drug;

Administration of a loading dose (LD) on both Day 1 and Day 2, or on Day1 only, followed by continuous QD dosing with the designated dose; or

Administration of continuous QD dosing without a loading dose.

Single-Dose Pharmacokinetics

Single dose (Day 1) pharmacokinetics of Compound were evaluated afteroral administration of Compound tablets under fasting conditions in theongoing FTIH study and preliminary results are depicted in Table 4.Plasma concentrations for Compound were not measurable for all subjectsover the 24-hour time period, especially for subjects administered lowdoses ranging from 0.125-0.50 mg. In general, AUC (0-24) and Cmax valueswere dose proportional up to 6 mg, lower than dose proportionalfollowing 8 mg and greater than dose proportional following the 10 mgdose. Most subjects had samples taken up to 24 hrs following single doseand half-life and AUC (0-inf) could not be calculated. Median Tmaxranged from 1.0 to 3.0 hours. Mean variability (CV %) in exposure rangedfrom 13 to 68% for Cmax and 12 to 56% for AUC (0-24) across all dosingregimens.

TABLE 4 Preliminary Pharmacokinetic Parameters Following Single DoseAdministration of Compound (Day 1) Dose AUC (0-24) Cmax Tmax C24 (mg) N(ng * hr/mL) (ng/mL) (hr) (ng/mL) 0.125  2^(a) NA 0.62, 0   0.50, NA 0,0 0.25  1^(a) NA 0.34  1.03 0 0.5 2 2.13, 9.69 0.85, 1.21 1.5, 1.5   0,0.31 1.0 2 13.5, 12.2 1.71, 1.96 1.5, 1.5 0.38, 0.27 2.0 3 56.2 (33%)6.83 (26%) 1.5 1.49 (27%) (44.2-77.4) (5.40-8.81) (1.5-2.0) (1.15-1.93)2.5 9 71.1 (25%) 9.68 (32%) 1.5 1.81 (34%) (47.3-95.9) (6.70-16.2)(1.0-2.0) (1.25-3.10) 3.0 12  81.4 (54%) 11.5 (62%)  1.25  3.35 (101%)(27.6-188)  (2.82-22.9) (0.5-3.0) (0.75-13.4) 4.0 3 223 (24%) 27.1 (35%)1.0 8.77 (60%) (167-275) (16.3-34.2) (1.0-1.0) (5.53-14.9) 6.0^(b) 10 197 (46%) 23.2 (50%) 1.5 6.58 (41%) (96.7-320)  (6.91-37.2) (1.05-8.08) (3.4-11.1) 8.0^(b) 7 161 (56%) 14.9 (68%) 3.0 5.81 (50%) (62.9-308) (4.28-32.0)  (1.0-24.0) (2.98-12.1) 10.0^(b) 4 884 (12%) 78.7 (13%) 1.525.5 (15%) (773-979) (65.1-87.8) (1.0-2.0) (21.0-29.0) Abbreviations:BQL = Below quantitation limit of the assay; NA = Not available Note:Pharmacokinetic parameters listed for individuals if patient number <=2;listed as mean (CV %) and range if patient number >2; Tmax reported asmedian (range); T_(1/2) not displayed as a terminal phase could not beidentified g. Subjects in the low dose cohorts had limited samples (≦3quantifiable samples) and AUC is not reported; One subject had BQL forall samples h. Administered as loading dose on Day 1

Multiple-Dose Pharmacokinetics

Repeat dose (Day 15) pharmacokinetics of Compound were assessed afteroral administration of Compound tablets under fasting conditions in theFTIH study and preliminary results are depicted in Table 5. Compoundaccumulated with repeat daily dosing with a mean accumulation ratio atthe recommended dose of 2 mg QD of 6.6. Mean AUC (0-tau) and Cmax valueson Day 15 generally increased in a dose-proportional manner (i.e.,2-fold increase in dose resulted in a 2-fold increase in exposure). Dueto the long elimination phase, an effective half-life (T1/2, eff) ofapproximately 5 days was calculated based on the accumulation ratio.Between-subject variability (CV %) in exposure ranged from 27 to 50% forCmax and 20 to 41% for AUC (0-24) across all dosing regimens.

TABLE 5 Preliminary Pharmacokinetic Parameters Following Repeat DoseAdministration of Compound (Day 15) Dose AUC(0-24) Cmax Tmax C24 T1/2,eff (mg) N (ng · h/mL) (ng/mL) (h) (ng/mL) AR (days) 0.125 2 17.8, 14.61.21, 1.58  1.0, 1.5 0.66, 0.58 NA NA 0.25 1 31.1 2.08 1.5  1.16 NA NA0.50 2 60.1, 98.9 3.91, 5.38  2.1, 1.0 2.21, 4.29 28.3, 10.2 19.2, 6.7 1 2  243, 95.2 15.8, 7.96 0.75, 1.5 8.44, 19.1 18.1, 7.8  12.2, 5.1 2^(a)   12 376 (20%) 23.0 (27%) 1.75 12.3 (19%) 6.57 (36%) 4.20 (39%)(255-500) (14.1-32.9) (1.0-3.0) (8.26-16.9)   4.0-11.5) (2.43, 7.61)2.5^(a) 15 448 (41%) 26.7 (50%) 2.0  17.0 (53%) 8.14 (42%) 5.29 (45%)(215-865) (12.4-63.2) (1.0-24)  (6.86-40.5) (3.23-14.1) (1.87-9.40)3^(a)   14 575 (36%) 35.8 (39%) 2.10 19.5 (42%) 7.17 (64%) 4.60 (72%)(259-968) (15.6-60.9)  (0.5-10.0) (7.77-35.5) (1.50-17.8) (0.63-12.0) 4  2^(b) 549, 946 43.8, 62.8  1.5, 1.0 42.8, 8.01 2.42, 3.45 1.30, 2.02Abbreviations: AR = Accumulation Ratio; NA = Not applicable; T1/2, eff =Effective Half-Life Note: Pharmacokinetic parameters listed forindividuals if patient number <= 2; listed as mean (CV %), and (min-max)if patient number > 2; Tmax is reported as median (range). i. Containssubjects at both loading and continuous dosing regimens. j. Subject 1210omitted from analysis due to drug being withheld.

Additional blood samples were taken pre-dose on Day 15 of Cycle 1 andDay 1 of further cycles in Part 2 and Part 3 to assess steady statetrough levels of Compound. Mean trough concentrations after repeatdosing up to 10 cycles ranged from 10.0 to 18.9 ng/mL following 2.0 mgdaily and from 7.8 to 17.3 ng/mL following 2.5 mg. Mean (CV %) troughconcentrations on Day 15 after repeat dosing of 2.5 mg of Compound were16.8 ng/mL (54%) and ranged from 0.68 to 49.0 ng/mL.

After reviewing all available data, a dose of 2 mg administered oncedaily was selected based on tolerability, exposure-response relationshipwith pharmacodynamic markers in tumor biopsies, and clinical activity. A0.5 mg dose was also selected to accommodate lower strength dosing, forexample when used in combination with another anti-neoplastic compoundor when dose reduction is required due to toxicity.

Photostability of Drug Product

During the formulation development of Compound A, it was found that thelevel of two degradation products observed at RRT=0.81 and RRT=0.87 (byHPLC analysis) exceeded the ICH limit for unqualified impurities of 0.5%when exposed directly to ICH Q1B light conditions.

Coating Effect on Light Exposure

Uncoated tablets, 0.5, 1 and 2 mg were exposed to ICH Photostabilityconditions and tested to provide baseline impurity information forcomparison. Data in Table 6 shows that the impurities at RRT=0.81 andRRT=0.87 are greater than 0.5% for tablet cores prior to coating.

The composition of coatings studied is given in Table 7. Among the fivecoating formulations investigated, Opadry® white provided the leastamount of protection for 1 mg strength, as the observed impurity levelsappear to be similar to the uncoated tablets. Two different formulationsof Opadry® pink and Opadry® yellow were tested and all provided adequatelight protection.

Data from 1 mg showed that both formulations of Opadry® pink and yellowprovided adequate light protection. This protection does not change whenthe level of colorant is decreased from 4 to 2% w/w. With the protectionof Opadry® pink or yellow, all coated tablets demonstrated goodphotostability even under direct light exposure (tablets in Petri dish).

TABLE 6 Light Exposure of Core (Uncoated) Tablets in Petri Dish Impurity(% area) Impurity (% area) Impurity (% area) Strength (mg) RRT = 0.81RRT = 0.87 RRT = 0.89 0.5 0.73 0.90 0.07 1 0.50 0.61 <0.05 2 0.80 0.580.07

TABLE 7 Composition of Coatings Opadry Formulation (% w/w) White Pink 1Pink 2 Yellow 1 Yellow 2 Component (OY-S-28876) (YS-1-14762-A)(03B140009) (YS-1-12525-A) (03B120006) Hypromellose 3 cP — 29.50 — 32.58— Hypromellose 6 cP 63.00 29.50 63.00 32.58 63.00 Titanium dioxide 30.0031.04 29.00 21.79 28.00 Macrogol/PEG400  7.00 8.00  7.00 8.00  7.00Polysorbate 80 — 1.00 — 1.00 — Iron Oxide Red — 0.96  1.00 — — IronOxide Yellow — — — 4.05  2.00

TABLE 8 Light Exposure of Coated Tablet in Petri Dish Impurity (% area)Strength (mg) Coating RRT = 0.81 RRT = 0.87 RRT = 0.89 0.5 White 2.00.40 ND Yellow-2 0.94 0.08 ND Pink-1 0.16 0.19 ND Pink-2 0.14 0.16 <0.051 White 0.58 0.44 <0.05 Yellow-1 0.10 0.13 ND Yellow-2 0.10 0.13 NDPink-2 0.07 0.06 ND 2 Pink-1 0.09 <0.05 ND ND = Not detected.Impurity Characterization

Although three impurities were observed during photostability studies,impurities at RRT=0.81 and RRT=0.87 are present at significant levels,while level of the impurity RRT0.89 is below the ICH identificationthreshold. The structures of RRT=0.81 and RRT=0.87 were determined andare provided in Table 9. They hereby referred to as Impurity I andImpurity II, respectively.

TABLE 9 Structures of Impurities Code Name Structural Formula Impurity I(RRT 0.81)

Impurity II (RRT 0.87)

RRT 0.89 Structure is not determined

In view of the results depicted in Tables 6, 7 and 8, the color in thetablet coating appears to play an important role in protecting CompoundA from light degradation. The color coatings may prevent light inducedimpurities from being formed either by physically blocking the damagingwavelength or by providing chemical protection (scavenging oxidizingradicals).

As both pink and yellow Opadry® colors contained iron oxide and theOpadry® white did not; film coatings with a color containing iron oxideare anticipated to prevent light induced impurities in tabletscontaining Compound A.

As an alternative to film coatings containing a colorant (not white),uncoated tablets, wax coated tablets, white coated tablets and the like,can be placed in a protective light resistant blister pack or lightresistant bottle to keep the drug away from light.

Particle Size

The benefit of drug substance micronization and use of specifieddisintegrants to improve the exposure was confirmed with a pre-clinicalDMPK study. The variability of the pre-clinical exposure data usingun-micronized drug substance suspended in 0.5% methyl cellulose(“un-micronized” in Table 10 below) was deemed unacceptable (both withinand between studies). To test whether the variability in the exposurewas due to variability in uniformity of the dose as well as the surfacearea of the suspended solids, an experiment was performed to determinethe physical stability of suspensions made with un-micronized andmicronized drug substance; and with and without specified disintegrants.The results of this experiment suggested that in order to ensureadequate reproducibility of the suspension dose it is necessary to usemicronized drug substance. Suitably, the micronized drug substance isused with a specified disintegrant or specified disintegrants. Thesuspension made from un-micronized drug substance and without aspecified disintegrant, showed rapid sedimentation and increase inparticle size.

A suspension formulation was prepared from micronized drug substancesuspended in a vehicle consisting of 5% mannitol, 1.5% hypromellose and0.2% sodium lauryl sulfate (“micronized” in Table 10 below). Twoconcentrations were prepared: 26.9 mcg/mL and 134.4 mcg/mL and dosed thesame day. On the third day the 134.4 mcg/mL suspension was dosed againalong with a freshly prepared suspension of similar concentration Table10 summarizes the exposure data (AUC) and FIG. 1 represents the resultsof the pre-clinical studies.

TABLE 10 Exposure in Pre-clinical Rat Studies Area under the Curve (ng ×hr/ml) − Mean (S.D.) or [Range] Dose (mg/m²) Formulation 1 3 5 10 20 30un-micronized¹ 102  [69-140] un-micronized¹ 311 1081 505 [296-333][576-1352] [397-628] micronized Day 1 140 1712 C² (14) (158) Day 3 1646(403) Day 3 1888 NB (340) NB = New batch of suspension. ¹Un-micronizeddrug substance suspended in 0.5% Methylcellulose ²Micronized drugsubstance suspended in 1.5% hypromellose, 0.2% sodium lauryl sulfate, 5%mannitolFIG. 1—Exposure Data for Compound A in Pre-Clinical Studies.

The data in Table 10 and FIG. 1 indicate that both the mean exposure andreproducibility were significantly improved by using the micronizedsuspension, made form micronized drug substance. Suitably, themicronized drug substance is in a formulation with a specifieddisintegrant or specified disintegrants, suitably selected from one ormore of: sodium lauryl sulfate, colloidal silicon dioxide andcroscamellose sodium.

By the term micronized, as used herein, is meant the standard usage inthe art that the drug particles are processed, for example by milling,bashing and/or grinding, to significantly reduce particle size overthose produced naturally during chemical synthesis. Suitably for useherein, at least 50% of the subject particles are 30 micron or less,suitably at least 50% of the particles are 10 micron or less, suitablyat least 50% of the particles are 5 micron or less.

A suitable particle size distribution for the drug particles of theinvention are as follows.

-   -   X10: NLT 0.46 μm    -   X50: 1.0-4.2 μm    -   X90: NMT 10.6 μm

In one embodiment of the present invention, it was discovered that wetgranulation or a tabletting technique that uses a significant waterconcentration is unsuitable for preparing tablets of Compound A,particularly on a commercial scale, because upon contact with waterduring the formulation process, Compound A can revert to Compound Bwhich is significantly less soluble. Experiments were undertaken todetermine the acceptable level of the desolvated Compound B in apharmaceutical dosage form and the appropriate formulation techniques.

Desolvation

DMSO Content by HPLC

A gradient elution HPLC method was used to determine the DMSO content inTablets containing Compound A. The typical chromatographic conditionsare summarized in Table 11.

TABLE 11 Typical DMSO Content HPLC Instrument/Chromatographic ConditionsAnalytical Column Details Atlantis T3, 250 × 4.6 mm, 5 μm (Type,particle size and dimensions) (or validated alternative) ColumnTemperature 40° C. Mobile phase A 100% Water Mobile phase B 100%Acetonitrile Flow rate 1.0 mL/min Detector wavelength UV at 195 nmContent and Impurities Assay Time (min) % A % B Gradient Profile 0.0 1000 6.0 100 0 7.0 20 80 10.0 20 80 10.1 100 0 30.0 100 0 Injection volume5 μL Data collection time/reporting time 10 min Run Time 30 minutes

Stability data for 1 mg tablets containing Compound A, made generallyaccording to Example 2, exposed to four different storage conditions(30's count in HDPE Bottles with Desiccant) is presented in Table 12 andFIG. 2.

TABLE 12 Test DMSO Content Content (% % Dissolution (% Label ofDesolvation (% released) Claim) Compound A (Calculated)* Mean (min-max)Specification Storage Time Complies with USP Condition (Months)90.0-110.0% 9.0-13.5 NMT 20% Q = 75% at 30 min. Initial 0 99.1 11.3 0 95(92-98) 25° C./60% 3 98.8 11.0 2.65  97 (93-101) RH 6 100.6 10.8 4.42 92(90-95) 30° C./75% 3 98.5 10.9 3.54 91 (85-98) RH 6 99.9 10.6 6.19  95(91-100) 40° C./75% 1 98.7 10.8 4.42 94 (91-98) RH 3 99.3 10.2 9.73 94(89-99) 6 100.6 9.2 18.58 93 (90-96) 50° C. 1 99.3 10.3 8.85 94 (90-97)(ambient) 3 99.8 9.5 15.93  96 (93-100)

${\%\mspace{14mu}{desolvation}} = \frac{( {{{Initial}\mspace{14mu}{DMSO}\mspace{14mu}{content}} - {{current}\mspace{14mu}{DMSO}\mspace{14mu}{content}}} ) \times 100}{{Initial}\mspace{14mu}{DMSO}\mspace{14mu}{content}}$FIG. 2—Stability Data for 1 mg Tablets Containing Compound A

Extrapolated results show that the DMSO content lower limit correspondsto about 20% desolvation. Initial DMSO content corresponded to about 0%.Suitably, the initial DMSO content will be less than about 2%desolvation, suitably less than about 4% desolvation, suitably less thanabout 8% desolvation. Suitably, the DMSO content will not be less thanan equivalent of about 5% desolvation during the shelf life of thetablet, suitably about 10% desolvation suitably about 15% desolvation,suitably about 20% desolvation. Consequently, dry direct compression anddry granulation were found to be appropriate formulation techniques.

The solid oral pharmaceutical dosage forms, suitably tablets, suitablycapsules, of the present invention will typically be sized up to 1 gram,suitably from about 140 mg to about 175 mg. These solid dosage formswill contain Compound A in an amount selected from: 0.5 mg, 1 mg and 2mg, by weight of Compound B. Tablet formulations of the invention mayhave a variety of shapes, including: round, modified round, diamond,modified capsule, modified oval, oval and hexagonal, and may optionallyhave a tilt.

Tablets

The choice of particular types and amounts of excipients, and tablettingtechnique employed depends on the further properties of Compound A andthe excipients, e.g., compressibility, flowability, particle size,compatibility, and density. The tablets may be prepared according tomethods known in the art, including dry direct compression and drygranulation, and the type of excipients used will vary depending on theexact process employed. It has been found that dry direct compression isparticularly suitable for providing high strength, low breakage tabletscomprising relatively low concentrations of Compound A (e.g., less thanabout 1.5%, suitably less than 1%), on a scale suitable for commercialproduction. Suitable dry direct compression tablets of the inventioncomprise dry blend comprising Compound A and one or more of fillers,binders and disintegrants, mixed with additional filler, binder,disintegrant and/or lubricant to form a compression mixture that iscompressed to form tablets.

Included in the present invention are pharmaceutical compositions intablet form, suitably prepared on a commercial scale, that compriseCompound A, wherein the tablet is made by a dry direct compressionprocess using a diluent or diluents that are substantially free water.Also included in the present invention are such pharmaceuticalcompositions that contain a film coat, wherein the film coat contains acolored pigment.

Also included in the present invention are pharmaceutical compositionsthat comprise Compound A, wherein the tablet is made by a dry directcompression process, suitably on a commercial scale, using a diluent ordiluents that are substantially free water and the Compound A particlesare micronized.

The micronization of compound A enhances the biological exposure byincreasing the particle specific surface area, as well as providingadequate content uniformity of the low strength solid dosage form.

Additionally, the use of a surfactant as disclosed herein furtherenhances the biological exposure by increasing the wettability of themicronized compound A.

In one embodiment of the present invention, the tablets of the presentinvention comprise:

(i) from about 0.3% to 1.5% Compound A;

(ii) from about 25% to about 89% of diluent;

(iii) up to about 8% binder, suitably up to about 5%;

(iv) up to about 2% lubricant, suitably up to about 0.75%;

(v) from 2% to about 8% disintegrant, suitably 3%;

In the foregoing embodiments, the diluent is suitably a combination ofmannitol and microcrystalline cellulose, the binder is suitably HPMC,the lubricant is suitably magnesium stearate, and the disintegrant issuitably a combination of sodium lauryl sulfate, colloidal silicondioxide and croscamellose sodium.

In one embodiment of the current invention, tablets are coated with afilm coat formed from an aqueous film coat composition. Aqueous filmcoat compositions suitable for use in the present invention comprise afilm-forming polymer, water as a vehicle, and optionally one or moreadjuvants such as are known in the film-coating art. Suitably, the filmcoat will contain a colored pigment.

Suitably, the colored pigment contains iron oxide.

The film-forming polymer is selected to form coatings with mechanicalproperties (e.g., mechanical strength, flexibility) suitable to meetperformance requirements, such as those required by the intended useenvironment (e.g., dissolution profile in gastrointestinal fluids),and/or use (e.g. solution viscosity). Examples of suitable film-formingpolymers include cellulosic polymers (e.g., cellulose ethers such asHPMC, HPC, MC, EC, HEC, CAP, sodium ethyl cellulose sulfate,carboxymethyl cellulose and the like); polyvinylpyrolidone; zein; andacrylic polymers (e.g., methacrylic acid/methacrylic acid estercopolymers such as methacrylic acid/methylmethacrylate copolymers andthe like). Cellulosic polymers are preferred in the present invention,especially cellulosic ethers and more especially HPMC and HPC. Thepolymers are typically provided in either aqueous or organic solventbased solutions or aqueous dispersions. However, the polymers may beprovided in dry form, alone or in a powdery mixture with othercomponents (e.g., a plasticizer and/or colorant), which is made into asolution or dispersion by the user by admixing with the aqueous vehicle.

The aqueous film coat composition further comprises water as a vehiclefor the other components, to facilitate their delivery to the tabletsurface. The vehicle may optionally further comprise one or more watersoluble solvents, e.g., alcohols (e.g., methanol, isopropanol, propanol)and ketones (e.g., acetone). The skilled artisan can select appropriatevehicle components to provide good interaction between the film-formingpolymer and the vehicle to ensure good film properties. In general,polymer-vehicle interaction is designed to yield maximum polymer chainextension to produce films having the greatest cohesive strength andthus mechanical properties. The components are also selected to providegood deposition of the film-forming polymer onto the tablet surface,such that a coherent and adherent film is achieved.

The aqueous film coating composition may optionally comprise one or moreadjuvants known in the art, such as plasticizers, colorants,detackifiers, secondary film-forming polymers, flow aids, surfactants(e.g., to assist spreading), maltodextrin, and polydextrose.

Plasticizers provide flexibility to the film, which may reduce filmcracking and improve adhesion to the tablet. Suitable plasticizers willgenerally have a high degree of compatibility with the film-formingpolymer and sufficient permanence such that the coating properties aregenerally stable. Examples of suitable plasticizers include glycerin,propylene glycol, polyethylene glycols (e.g., molecular weight from 200to 20,000, including Union Carbide's PEG 400, 4000, 6000, 8000, and20,000), glycerin triacetate (aka triacetin), acetylated monoglyceride,citrate esters (e.g., triethyl citrate, acetyl triethyl citrate,tributyl citrate, acetyl tributyl citrate), phthalate esters (e.g.,diethyl phthalate), mineral oil and hydrogenated glucose syrup. In oneembodiment of the present invention, the plasticizer is chosen frompolyethylene glycols, triacetin, propylene glycol, glycerin, andmixtures thereof.

Compound A was found to be sensitive to photo-induced degradation. Afilm coating, suitably a colored film coating, is advantageous toimprove stability.

The aqueous film coat composition will typically comprise from about 5%to about 25%, suitably about 5% to about 20%, coating solids in thevehicle. In suitable embodiments, the solids typically comprise fromabout 25% to about 70%, suitably about % to about 70% film-formingpolymer, about 5% to about 10%, suitably about 6% to about 8%,plasticizer, and about 20% to about 35% pigment and colorant, by weight.In suitable embodiments, the colorant comprises from about 0.5 to 3% byweight.

A number of suitable aqueous film coating compositions are commerciallyavailable. The aqueous film coat composition may be provided in the formof a solution or dispersion. Alternatively, the composition may beprovided in a dry form that can be combined with the vehicle componentsaccording to supplier instructions prior to coating the tablet.Suitably, aqueous film coating compositions are those commerciallyavailable from Colorcon, Inc. of West Point, Pa., under the trade nameOPADRY and OPADRY II (nonlimiting examples include Opadry PinkYS-1-14762-A or 03B140009, Opadry Yellow YS-1-12525-A or 03B120006).These compositions are available as dry film coating compositions thatcan be diluted in water shortly before use.

The tablets are also suitably coated to provide a uniform coatingwithout speckling. The tablets are typically coated to provide a drytablet weight gain of from about 2 to about 5%, suitably about 2.5 to4%.

The uncoated tablet cores are coated with the aqueous film coatingcomposition by methods well known in the art using commerciallyavailable equipment (e.g., Thomas Accela-Cota, Vector Hi-Coater,Compu-Lab 36). In general, the process usually involves rolling ortumbling the tablets in a pan, or suspending the tablets on a cushion ofair (fluidized bed), and intermittently or continuously (preferablycontinuously) spraying a fine mist of atomized droplets of the coatingcomposition onto the tablets, the droplets wetting, spreading andcoalescing on the surface of the tablets to form an adherent andcoherent film coating. The tablets are typically heated to about 40 to50° C., suitably about 45 to 50° C., e.g., by air having a temperatureof up to about 85° C., suitably about 65 to 80° C.

The invented solid oral pharmaceutical dosage forms may be administeredin therapeutically effective amounts to treat or prevent a diseasestate, e.g., as described in the above referenced InternationalApplication No. PCT/JP2005/011082, and United States Patent PublicationNo. US 2006/0014768.

A method of this invention of inhibiting MEK activity in humanscomprises administering to a subject in need of such activity atherapeutically effective amount of a solid oral pharmaceutical dosageform of the present invention.

The invention also provides for the use of Compound A in the manufactureof a solid oral pharmaceutical dosage form of the present invention.

The invention also provides for the use of Compound A in the manufactureof a solid oral pharmaceutical dosage form of the present invention foruse in treating cancer.

The invention also provides for the use of Compound A in the manufactureof a solid oral pharmaceutical dosage form of the present invention foruse in inhibiting MEK.

The invention also provides for a solid oral pharmaceutical dosage formfor use as a MEK inhibitor which comprises Compound A and apharmaceutically acceptable carrier of the present invention.

The invention also provides for a solid oral pharmaceutical dosage formfor use in the treatment of cancer which comprises Compound A and apharmaceutically acceptable carrier of the present invention.

The invention also provides for a solid oral pharmaceutical dosage formfor use in inhibition MEK which comprises Compound A and apharmaceutically acceptable carrier of the present invention.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following Examples, therefore, are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention.

All the excipients utilized herein are standard pharmaceutical gradeexcipients available from numerous manufacturers well known to those inthe art.

EXAMPLES Examples 1 to 3 Tablet Preparation

Dry direct compression, tablets comprising Compound A and theingredients in Table 13 were prepared.

TABLE 13 Strength (mg, as Compound B) Component 0.5 1 2 Compound A,micronized¹ 0.5635 1.127 2.254 Sodium Lauryl Sulfate 0.017 0.034 0.068Colloidal Silicon Dioxide 0.010 0.020 0.040 Mannitol 95.47 101.509106.95 Microcrystalline Cellulose 36.25 38.75 41.25 Hypromellose 7.257.75 8.25 Croscarmellose Sodium 4.35 4.65 4.95 Magnesium Stearate 1.091.16 1.24 Opadry Pink YS-1-14762-A NP NP 4.95 Opadry Yellow YS-1-12525-A4.35 NP NP Opadry White OY-S-28876 NP 4.65 NP Purified Water² — — —Total Tablet Weight 149.35 159.65 169.95 Note: ¹The amount of Compound Arequired to achieve the label claim of Compound B (the free orun-solvated compound) is calculated utilizing the molecular conversionfactor of 0.8873 for the ratio of Compound B (un-solvated) to compound A(the DMSO solvate), and based on the purity value from the certificateof analysis. The amount of Mannitol is adjusted accordingly. ²Water isremoved during processing. NP = not present in formulation.Blending

The micronized drug substance, sodium lauryl sulfate, silicon dioxide,croscarmellose sodium, microcrystalline cellulose and hypromellose arescreened, if required, and transferred into a suitable bin blender andblended. The magnesium stearate is screened, if required, transferred tothe bin blender and blended for an additional time.

Compression

The lubricated blend is compressed on a rotary tablet press to thetarget weight for each strength (145 mg, 155 mg and 165 mg correspondingto 0.5 mg, 1 mg and 2 mg, respectively). The compressed tablets aresampled for in-process monitoring of individual weight variation,appearance, hardness, thickness, friability and disintegration time.

Coating

Tablet cores are sprayed with an aqueous suspension of Opadry® PinkYS-1-14762-A) (for 2 mg strength), Opadry® Yellow YS-1-12525-A (for 0.5mg strength) or Opadry® White OY-S-28876 (for 1 mg strength). Coatingcontinues until a target weight gain of approximately 3% is attained.The tablets are then dried and bulk packed into HDPE containers withplastic liners and desiccant bags, and stored until packaged.

While the preferred embodiments of the invention are illustrated by theabove, it is to be understood that the invention is not limited to theprecise instructions herein disclosed and that the right to allmodifications corning within the scope of the following claims isreserved.

What is claimed is:
 1. A pharmaceutical tablet comprising: a) an amountof a drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) the tablet contains from about 25%to about 89% by weight of one or more excipients, where the excipientsare substantially free of water.
 2. The pharmaceutical tablet, accordingto claim 1, comprising: a) an amount of a drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethyl sulfoxidesolvate, selected from: about 0.5635 mg, about 1.127 mg, and about 2.254mg; wherein, b) the drug particles are micronized; c) the tabletcontains from about 25% to about 89% by weight of one or moreexcipients, where the excipients are substantially free of water.
 3. Thepharmaceutical tablet, according to claim 1, comprising: a) an amount ofa drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethyl sulfoxidesolvate, selected from: about 0.5635 mg, about 1.127 mg, and about 2.254mg; wherein, b) the drug particles are micronized; c) the tabletcontains from about 25% to about 89% by weight of one or more excipientsselected from: microcrystalline cellulose, powdered cellulose,pregelatinized starch, starch, lactose, Di-calcium phosphate, lactitol,mannitol, sorbitol and maltodextrin, where the excipients aresubstantially free of water.
 4. The pharmaceutical tablet, according toclaim 1, comprising: a) an amount of a drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) the drug particles are micronized;c) the tablet contains from about 25% to about 89% by weight of one ormore excipients selected from: microcrystalline cellulose, powderedcellulose, pregelatinized starch, starch, lactose, Di-calcium phosphate,lactitol, mannitol, sorbitol and maltodextrin, where the excipients aresubstantially free of water; and d) the tablet is film coated.
 5. Thepharmaceutical tablet, according to claim 1, comprising: a) an amount ofa drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethyl sulfoxidesolvate, selected from: about 0.5635 mg, about 1.127 mg, and about 2.254mg; wherein, b) the drug particles are micronized; c) the tablet isproduced on a scale suitable to prepare at least about 50,000 tablets;d) the tablet contains from about 25% to about 89% by weight of one ormore excipients selected from: microcrystalline cellulose, powderedcellulose, pregelatinized starch, starch, lactose, Di-calcium phosphate,lactitol, mannitol, sorbitol and maltodextrin, where the excipients aresubstantially free of water; and e) the tablet is film coated.
 6. Thepharmaceutical tablet, according to claim 1, comprising: a) an amount ofa drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) the drug particles are micronized;c) the tablet is produced on a scale suitable to prepare at least about50,000 tablets; d) the tablet contains from about 25% to about 89% byweight of one or more excipients selected from: microcrystallinecellulose, powdered cellulose, pregelatinized starch, starch, lactose,Di-calcium phosphate, lactitol, mannitol, sorbitol and maltodextrin,where the excipients are substantially free of water; and f) the tabletis film coated and wherein the film coating contains a colorant.
 7. Thepharmaceutical tablet, according to claim 1, comprising: a) an amount ofa drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) the drug particles are micronized;c) the tablet is produced on a scale suitable to prepare at least about50,000 tablets; d) the tablet contains from about 25% to about 89% byweight of one or more excipients selected from: microcrystallinecellulose, powdered cellulose, pregelatinized starch, starch, lactose,Di-calcium phosphate, lactitol, mannitol, sorbitol and maltodextrin,where the excipients are substantially free of water; and e) the tabletis film coated and wherein the film coating contains a colorant thatcontains iron oxide.
 8. A pharmaceutical tablet comprising: a) an amountof a drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) at least 50% of the drug particleshave a particle size of 30 micron or less; and c) the tablet containsfrom about 25% to about 89% by weight of one or more excipients, wherethe excipients are substantially free of water.
 9. The pharmaceuticaltablet, according to claim 8, comprising: a) an amount of a drug, whichisN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) at least 50% of the drug particleshave a particle size of 30 micron or less; and c) the tablet containsfrom about 25% to about 89% by weight of one or more excipients selectedfrom: microcrystalline cellulose, powdered cellulose, pregelatinizedstarch, starch, lactose, Di-calcium phosphate, lactitol, mannitol,sorbitol and maltodextrin, where the excipients are substantially freeof water.
 10. The pharmaceutical tablet, according to claim 8,comprising: a) an amount of a drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) at least 50% of the drug particleshave a particle size of 30 micron or less; c) the tablet contains fromabout 25% to about 89% by weight of one or more excipients selectedfrom: microcrystalline cellulose, powdered cellulose, pregelatinizedstarch, starch, lactose, Di-calcium phosphate, lactitol, mannitol,sorbitol and maltodextrin, where the excipients are substantially freeof water; and d) the tablet is film coated.
 11. The pharmaceuticaltablet, according to claim 8, comprising: a) an amount of a drug, whichisN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) at least 50% of the drug particleshave a particle size of 30 micron or less; c) the tablet is produced ona scale suitable to prepare at least about 50,000 tablets; d) the tabletcontains from about 25% to about 89% by weight of one or more excipientsselected from: microcrystalline cellulose, powdered cellulose,pregelatinized starch, starch, lactose, Di-calcium phosphate, lactitol,mannitol, sorbitol and maltodextrin, where the excipients aresubstantially free of water; and d) the tablet is film coated.
 12. Thepharmaceutical tablet, according to claim 8, comprising: a) an amount ofa drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) at least 50% of the drug particleshave a particle size of 30 micron or less; c) the tablet is produced ona scale suitable to prepare at least about 50,000 tablets; d) the tabletcontains from about 25% to about 89% by weight of one or more excipientsselected from: microcrystalline cellulose, powdered cellulose,pregelatinized starch, starch, lactose, Di-calcium phosphate, lactitol,mannitol, sorbitol and maltodextrin, where the excipients aresubstantially free of water; e) the tablet is film coated and whereinthe film coating contains a colorant.
 13. The pharmaceutical tablet,according to claim 8, comprising: a) an amount of a drug, which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg; wherein, b) at least 50% of the drug particleshave a particle size of 30 micron or less; c) the tablet contains fromabout 25% to about 89% by weight of one or more excipients, where theexcipients are substantially free of water; and d) the tablet is filmcoated and wherein the film coating contains a colorant that containsiron oxide.
 14. The pharmaceutical tablet according to claim 6 wherein:the tablet contains from about 25% to about 89% by weight of one or moreexcipients selected from: microcrystalline cellulose and mannitol. 15.The pharmaceutical tablet according to claim 9 wherein: the tabletcontains from about 25% to about 89% by weight of one or more excipientsselected from: microcrystalline cellulose and mannitol.
 16. A processfor preparing pharmaceutical tablets containing an amount of a drug,which isN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, selected from: about 0.5635 mg, about 1.127mg, and about 2.254 mg, which process comprises the steps of; admixing:N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate, one or more excipients, where the excipientsare substantially free of water, and further excipients, to form amixture; and compressing the mixture into tablets; provided: each tabletcontainsN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide solvate in an amount selected from: about 0.5635 mg,about 1.127 mg, and about 2.254 mg; and each tablet contains from about25% to about 89% by weight of one or more excipients, where theexcipients are substantially free of water.